The goal of our research is to elucidate mechanisms by which glucocorticoids (GC's) of the adrenal cortex mediate adaptive and maladaptive effects of stress on the brain. The pituitary-adrenal axis is essential for the adaptation to stress, because, without it, animals are extremely vulnerable to a variety of stressors; and yet this axis is also the mediator of damaging effects, such as immunosuppression and loss of neurons in vulnerable brain structures like the hippocampus. In 1968, we discovered that the hippocampus contains receptor sites for adrenal steroids. Subsequent studies have shown that there are two types of receptors in the brain, one concentrated in the hippocampus and the other more widespread. Accumulating evidence indicates that the hippocampus participates in control of pituitary-adrenal function, and our recent studies have focused on the stress-elevation of circulating GC's which synergize with ongoing neural activity to alter brain morphology and neurochemistry. GC effects on the brain are of two types: 1) Effects which counteract and thereby buffer against the primary neural reactions to stress, as in the case of noradrenergic, serotonergic and benzodiazepine systems; 2) Effects which lead to damage and destruction of neural tissue, particularly via interactions with excitatory amino acids and their receptors. The goals of our projected research are to clearly establish and characterize neurochemical, molecular and morphological effects of GC's in the hippocampus and related brain regions and then to establish the time course over which they mediate brain changes resulting from uncontrollable as well as controllable stress. We shall also begin to assess developmental determinants of the neural systems upon which these GC actions take place, by examining the effects of prenatal stress and postnatal "handling". We will also examine the influence of stress and hippocampal input on neurons of the paraventricular nuclei of the hypothalamus which produce corticotrophin releasing hormone and vasopressin that regulate ACTH secretion from the pituitary. This work is particularly relevant because stress is a likely factor in precipitating depressive illness, as well as in increasing vulnerability to tumors and infections by altering neural and endocrine outputs that affect the immune system. Our working hypothesis is that depressive illness represents a failure of normal adaptive mechanisms to operate, and that GC's are the body's own antidepressant agent - or at least one of them. We feel that by understanding the normal adaptive mechanisms to stress in terms of biochemical and morphological changes in the brain, we will be better prepared to recognize what goes wrong when adaptation fails. Besides relating to depressive illness, the effects of GC's on the survival and destruction of neurons, particularly in hippocampus, raises the possibility that the course of Alzheimer's disease and other neural degenerative diseases may be accelerated by stress. Better understanding of the beneficial as well as destructive aspects of GC actions on neuronal survival may aid in developing treatment strategies to slow the rate of progress of neural degenerative diseases.